National Human Genome Research Institute (NHGRI)

GLP-1 receptor agonists (GLP-1R agonists or GLP-1RAs) are a class of drugs that mimic the human GLP-1 hormone to manage type 2 diabetes and obesity, that are being taken by millions of Americans. However, not all people respond to GLP-1RAs. One explanation is genetic variation in GLP-1R. Over 500 genetic variants of GLP-1R have been described in the human population. This project aims to characterize how these variant GLP-1R proteins vary in their sensitivity to GLP-1RAs.

Some GLP-1RA drugs are based on a naturally occurring component of Gila monster venom, exendin-4. Gila monsters have two other homologs of GLP-1. Evidence suggests that exendin-4 may have evolved as a defensive peptide in Gila monsters against predators (largely mammals). The specificity and longevity of the Gila monster exendin-4 against the variation that exists across vertebrate species is still an open question, and will also be characterized in this project. 

The human body is colonised by a diverse community of commensal microorganisms (bacteria, fungi, viruses) with beneficial roles to human health. However, many microbial species naturally inhabiting body sites such as the skin and gut also have the potential to cause disease. In this project, we aim to integrate  bioinformatics, microbiology, metagenomics (genetics and genomics) and immunology to advance our understanding of the role of the human microbiome in health and disease. A key focus of our research is developing and applying new methods for strain-level resolution and exploring how the microbiome influences the emergence of antimicrobial-resistant pathogens. Ultimately, this research could inform new therapeutic strategies to combat infections and promote microbiome-based interventions for improved health outcomes over a human lifespan.

Many pathogens can infect a wide range of potential hosts. Understanding the factors that control pathogen host range is critical for understanding host-pathogen biology and for identifying potential reservoirs of disease. A major determinant of a pathogen’s host range is the compatibility between the pathogen’s effectors and key host proteins, such as host receptors required for infection or host immune proteins whose function the pathogen specifically neutralizes. We are developing and utilizing a new approach to systematically explore which animals carry host proteins that are susceptible to particular pathogen effectors. For a known targeted host protein, we identify thousands of homologs from across the space of sequenced genomes, and then synthesize the surface of the homologs bound by the effector and test whether the effector can bind them.

This project will involve selecting an important human pathogen, such as malaria, HIV, plague, or any other pathogen of interest to the student, and applying our systematic approach to determining its potential host range. We are also interested in exploring other applications of this novel approach, such as testing a single host protein against a range of pathogen effectors to determine the space of potential future pathogens. Please get in touch if you have ideas anywhere in this space!

Population genomic approaches across diverse species have traditionally used short read sequence data to investigate population structure and signatures of selection. In the recent past, long reads are more traditionally used to build reference genomes to which the short read data can be aligned and evaluated. However, the cost of long read sequencing as well as the DNA input required to generate high quality long read data is dropping rapidly. We foresee a future where population genomics transitions to long read data.

Using these emerging technologies, this project will begin to evaluate what new insights are gained for the Anopheles gambiae species complex, a set of mosquito species famous as the vector of malaria and known to exhibit porous species boundaries and abundant structural variation.  We anticipate that long-read approaches for haplotype phasing and structural variant discovery will enable much clearer resolution of gene flow within species, introgression between species, and alleles under directional or balancing selection.  Insights gained from this project are likely to influence approaches taken for other species that are known to have similar complexities (e.g., Heliconius butterflies, African cichlid fishes).

This project will involve developing and applying new computational methods for analysing long-read sequencing data in an Anopheles population genomics context. The collaborating laboratories at the Sanger Institute and NHGRI are experts in these respective areas and well-suited to provide the appropriate mentorship.